Platelet-derived growth factor (PDGF) is a potent mitogen for cells of mesenchymal origin. It consists of homo-E heterodimers of PDGF A and PDGF B chains. All three possible isoterms of PDGF have been identified (AA, BB, AB), and they have been shown to bind to two different but related receptor molecules, designated alphaPDGFR and betaPDGFR. The alphaPDGFR binds to all three isoforms of PDGF, while the betaPDGFR exhibits high affinity binding only for PDGF BB. We utilized these different ligand binding specificities to investigate the PDGF AA binding site in the human alphaPDGF receptor by constructing chimeric molecules between the human alphaPDGFR and betaPDGFR. Our results demonstrate that amino acids 1 to 340 of the alphaPDGFR comprise the region of the extracellular domain at the alphaPDGFR that confers PDGF AA binding specificities. We have also investigated the role of alphaPDGFR's kinase insert. Our results indicate that deletions of the kinase insert region alters the gross structure of kinase domain in a manner that affects multiple functions of the receptor molecules and that its primary importance may be in maintaining the structural feature of the kinase domain.